Steroidal sulfonium salts



I carbon atoms. vention at least one of the lower alkyl radicals is methyl.

STEROIDAL SULFONIUM SALTS Raymond M. Dodson, Park Ridge, and Paul B. Sollman, Skokie, lll., assignors to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware No Drawing. Application June 6, 1956 Serial No. 589,600

13 Claims. (Cl. 260-3973) The present invention relates to steroidal sulfonium salts. It is particularly concerned with compounds of the general structural formula S (lower) alkyl Ha and with compounds of the general structural formula (lower)alkyl s -(lower)alkyl CH3 wherein X" is one equivalent of a non-toxic anion. These general formulas are not to be interpreted as expressing limitations with respect to the configurations of the valence bonds directed from, or the groups bonded to, the sulfur atom, as there are comprehended in this invention stereoisomers of both the 170: and 175 series, as well as stereoisomers which can result when the designated alkyl groups are not identical.

In the foregoing structural representations the lower alkyl groups can be selected from among straightand branched-chain alkyl radicals containing fewer than nine In the preferred embodiments of this in- Suitable starting materials for the manufacture of compositions of the present invention are the l7-alkylthio-5- androsten-3-ols described in our copending application, Serial No. 485,606, filed February 1, 1955, now US.

Patent No. 2,753,361, and the l7-alkylthio-4-androsten- 3-ones, described in our copending application, Serial No. 491,507, filed March 1, 1955, now US. Patent No. 2,763,669.

Upon reaction of a thioether of one of the designated classes, suitable in an inert organic solvent, with a lower alkyl halide, there is obtained a sulfonium salt of the type described and claimed herein. In the selection of reaction conditions for sulfonium salt formation, relatively mild conditions are employed when the substituent at steroidal position 17 is 'a 'methylthio group and the alkyl halide is methyl iodide, whereas progressively more drastic condithiQ-S-androsten-Bp-QI .methobromide.

tions, such as higher temperatures and longer heating periods, are advisable when either of the alkyl groups is other than methyl, or the halogen atom is bromine, or especially chlorine. Representative reaction conditions are set forth more fully in the examples to follow.

It will be apparent that the lower alkyl groups attached to the sulfur atom of the sulfoniumsalts are equivalently bonded to the sulfur atom, regardless of the convention by which the compounds are named. For example, a typical sulfonium salt of this invention, representable by the structural formula can be named as l7fi-methylthio-4-androsten-3-one ethiodide, as l7,6-ethylthio-4-androsten-3-one methiodide, or as (3-oxo-4-androsten-17p-yl)methylethylsulfonium iodide.

Other sulfonium salts comprehended herein can be manufactured by the reaction of the corresponding sulfonium halide with a reagent favorable to anion interchange. Thus, by reaction of 17 3-methylthio-4-androsten-3-one methiodide with silver sulfate in aqueous medium there occurs a precipitation of silver iodide, and (3-oxo-4-androsten-l7B-yl)dimethylsulfonium sulfate is recovered from the aqueous solution. Upon admixture of aqueous solutions of this compound with stoichiometric quantities of water-soluble barium salts, there occurs precipitation of barium sulfate and the formation of other sulfonium salts of this invention.

The compositions of the present invention are valuable therapeutic agents because of their relatively high water solubility and their selective pharmacological actions. They have valuable antibacterial properties and are etfective, for example, against Bacillus subtilis. These sulfonium salts are anticholinergic agents capable of blocking the transmission of nerve impulses across the autonomic ganglia, and because of this property are valuable in the treatment of ulcers and other gastrointestinal dysfunctions associated with autonomic hyperactivity. They have anti-fibrillatory properties, and restore normal cardiac rhythm in conditions of atrial arrhythmia.

This invention will appear more fully from the ex amples which follow. These examples are set forth-by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many medi fications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight.

Example 1 A solution prepared from 24 parts of 17a-methylthio- 5-androsten-3 3-ol, parts of butanone, and 205 parts of methyl bromideis placed in a tightly sealed reaction vessel, and allowed to stand for 16 hours at65 C. The material which crystallizes from the solution is removed by filtration and is recrystallized from water. It is further purified by dissolving it in 1000 parts of hot alcohol and precipitating by the addition of 1000..parts of peroxide-free ether. This compound, is. flat-methyl- It melts. with ,decomposition at 188-189 C.,and has the following structural formula -cm i cm .Br-

Example 2 Methanol (80 parts) maintained at about 25' C. is saturated with methyl chloride; l7a-methylthio-4-androsten-S-one (3 parts) is added, and the resulting reaction CH: g C H: CH: i

Example 3 A solution of 6 parts of l7B-methylthio-4-androsten ,3-one', 200 parts of methanol and 220 parts of methyl iodide is heated under reflux in a nitrogen atmosphere for 3 hours, after which it is concentrated to dryness under reduced pressure. Excessive heating is avoided.

The residue is purified by crystallization from mixtures" of methanol and anhydrous ether and then from a mixture of methanol and butanone to afford 17fi-methylthio- 4-andosten-3-one methiodide which melts at about Example 4 By the procedure of Example 3, with the substitution of 190 parts of ethyl iodide for the methyl iodide, there is obtained 17,5ethy1thio-4-androsten-3-one methiodide.

Example 5 Example 6 A solution prepared from 5 parts of l7fl-methylthio- "4-androsten-3-one, parts of butanone and 85 parts of methyl bromide is placed in a tightly sealed reaction "vesseL-an'd allowed to stand for 24 hours at about 65' "heated under reflux for 30 minutes.

13.58 microns.

C. The insoluble reaction product is then collected on a filter and purified by recrystallization from a mixture of absolute ethanol and anhydrous ether and then from water. This product is l7p-methylthio-4-androsten-3- one methobromide. It melts at about 183-184 C.

Example 7 By the procedure of Example 6, with the substitution of 5 parts of l7a-methylthio-4-androsten-3-one for the 17B-methylthio-4-androsten-3-one, there is obtained 17- methylthio-4-androsten-3-one methobromide.

Example 8 A solution of 9.3 parts of 3p-hydroxy-5-androstene- 175-thio1 in 240 parts of methanol containing 1.6 parts of sodium methoxide is treated by the addition of 6 parts of propyl iodide, and the resulting mixture is The cooled mi'rtture is then filtered, and the filtrate is diluted with water until separation of the insoluble reaction productfiie complete. This product is collected and recrystallized from aqueous methanol to afiord purified l7fl-propy1- thio-5-androsten-3fl-o1 which melts at about 127-129 C. and has the structural formula 5 C CH: CH: CH;

Example 9 A solution of 4 parts of 17p-propylthio-S-androsten- 35-01, parts of methanol and parts of methyl iodide is heated under reflux in a nitrogen atmosphere for about 10 hours, after which it is rapidly diluted with 1700 parts of anhydrous ether. The crystalline product is collected on a filter and recrystallized from a mixture of methanol and ether to afiord 17fl-propylthio-5-androsten-3;8-ol methiodide. This composition shows a melting point, variable with the rate of heating, of approximately C., and a specific rotation of about 49.4' in methanol solution. Infrared absorption maxima are observed at about 2.93, 6.87, 6.98, 7.14, 9.48, 10.44, and

Example 10 f A solution of 46 parts of l7B-methylthio-4-androsten- S-one methiodide in 20,000 parts of water is mixed with a solution of 15.6 parts of silver sulfate in 2500 parts of water, and the precipitated silver iodide is removed by filtration. The filtrate is concentrated to about 3-4% 'of its original volume and diluted with 35,000 parts of acetone. The solid product which precipitates is collected on a filter and recrystallized by dissolving it in a minimum quantity of water and diluting with acetone. The product thus obtained is the sulfonium sulfate (3-oxo-4-androsten- 17B-yl)dimethylsulfonium sulfate which melts at about 158-160 C. and has the structural formula What is claimed is:

1. A member of the group consisting of compound: of

the structural formula S 1 8 (lower)a1ky and compounds of the structural formula 1 cm (lower)a.lky

wherein X- is one equivalent of a non-toxic anion.

2. 17p-( lower) alkylthio 4 androsten 3 one methohalide.

3. 17 p-(lowenalkylthio 4 androsten 3 one methobromide. 5 4. 17fi-methylthio-4-androsten-3-one methobromide.

5. 17a-(lower) alkylthio 4 androsten 3 one methohalide.

6. 17a-(lower)-alkylthio-4 androsten 3 one methobromide. 7. 17a-methylthio-4-androsten-3-one methobromide.

8. 17fl-(1ower) alkylthio 5 androsten 3B o1 methohalide.

9. l7p-(lower)alkylthio 5 androsten 3p ol methobromide. 10. 17p-methylthio-5-androsten-3B-ol methobromide.

11. 17a-(lower-alkylthio 5 androsten 3p o1 methohalide.

12. 17a-(1ower)a1ky1thio-5 androsten 3p ol methobromide. 20 13. 17a-methylthio-5-androsten-3fl-ol methobromide.

References Cited in the file of this patent UNITED STATES PATENTS Dodson et a1 July 3, 1956 Dodson et a1. Sept. 18, 1956 OTHER REFERENCES 

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE STRUCTURAL FORMULA 